Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

• the present invention is concerned with compounds of the formula ##STR2## wherein R 1 is lower alkoxy;
• R 2 is hydroxy or lower alkoxy
• R 3 is hydrogen, cyano, lower alkyl, alkenyl, cycloalkyl, bicyclyl, aryl, heterocyclyl, heteroaryl, aryl-Q-alkyl, or a group of the formula-CR 4 R 4 'COR 5 ;
• Q is --SO-- or SO 2 ;
• R 4 , R 4 ' are each independently hydrogen, alkyl, aryl or heterocyclyl
• R 5 is hydrogen, alkyl, alkoxy, aryl or heterocyclyl or hydroxy, or
• R 4 and R 5 together form --(CH 2 ) n --
• n is a whole number between 2 to 5 inclusive
• lower alkoxy, lower alkyl, alkyl, and cycloalkyl are unsubstituted or substituted by one or more groups selected from amino, dialkylamino, morpholino, piperidino, piperazino, hydroxy which is optionally esterified by an amino acid or sulfuric acid, halide, nitrile, thiocyanato, sulfato, lower-alkylsulphanoyl, oxo, carboxy, carbamino, carbalkoxy, carbamoyloxy, alkoxy, morpholinoalkoxy, piperidinoalkoxy, and cycloalkyl which is unsubstituted or substituted by one or more groups as defined above;
• aryl, heterocyclyl and heteroaryl are unsubstituted or substituted by one or more groups selected from phenyl, lower alkyl which is unsubstituted or substituted by one or more groups as defined above, cycloalkyl which is unsubstituted or substituted by one or more groups as defined above, hydroxy, cyano, thiocyanato, amino, halide, oxo, lower alkoxy which is unsubstituted or substituted by one or more groups as defined above, lower alkoxycarbonyl, di(lower alkyl)amino, carbamoyl, mono- or di-lower alkylcarbamoyl, lower alkylsulfanoyl, lower alkylsulfonyl, sulfamoyl, N-mono- or di-lower alkylsulfamoyl, heterocyclyl which is unsubstituted or substituted by one or more groups as defined above, or hetero
• alkenyl is unsubstituted or substituted by one or more substituents selected from the group cyano, acryloyl, and heteroaryl which is unsubstituted or substituted by one or more groups as defined above;
• the compounds of formula I are novel and possess valuable antibiotic properties. They can be used for the control or prevention of infectious diseases. In particular, they exhibit a pronounced antibacterial activity even against multiresistant, gram-positive strains and against resistant pneumococci and opportunistic pathogens such e.g. Pneumocystis carinii.
• the compounds of formula I can also be administered in combination with known antibacterially-active substances and then exhibit synergistic effects.
• Typical combination partners are e.g. sulfonamides, with which the compounds of formula I or their salts can be admixed in various ratios.
• Examples of sulfonamides which can be combined with the compounds of the present invention can be selected from the group sulfadiazine, sulfamethoxazole, sulfatroxazole, sulfamerazine, sulfadoxine, sulfadimethoxine, sulfamethazine, sulfapyrazole, sulfaquinoxaline, sulfachloropyridazine, sulfaguanidine, sulfalene, sulfametin, sulfamethoxine, sulfamethoxy-pyridazine, sulfamethylphenazole, sulfaphenazole, sulfamoxole, sulfapyrazine, sulfapyridazine, sulfapyridine, sulfasymazine, sulfathiozole,
• Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts per se and for use as therapeutically active substances, medicaments based on these substances, optionally in combination with sulphonamides, and their production; the use of these substances as medicaments and for the production of antibacterially-active medicaments; as well as making the compounds of formula I and their pharmaceutically acceptable salts and intermediates for their making the compounds.
• lower alkyl and “lower alkoxy” embrace-chain or branched alkyl and, respectively, alkoxy groups which have from 1 to 8 and preferably 1-4 carbon atoms and which are optionally substituted by one or more substituents, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.butyl, n-pentyl and n-hexyl; and, respectively, methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, isobutyloxy, and tert.butoxy.
• substituents such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.butyl, n-pentyl and n-hexyl; and, respectively, methoxy, ethoxy
• Suitable substituents for these alkyl and alkoxy groups are functional groups such as, for example, amino, dialkylamino, morpholino, piperidino, piperazino, hydroxy, halide, nitrile, thiocyanato, sulfato, lower alkyl sulphanoyl (e.g., methylsulfanyl), oxo, carbamoyloxy, carboxy, carbamino or carbalkoxy groups or substituents such as alkoxy, morpholinoalkoxy, piperidinoalkoxy and cycloalkyl.
• functional groups such as, for example, amino, dialkylamino, morpholino, piperidino, piperazino, hydroxy, halide, nitrile, thiocyanato, sulfato, lower alkyl sulphanoyl (e.g., methylsulfanyl), oxo, carbamoyloxy, carboxy, carb
• Methoxymethyl, hydroxymethyl, hydroxybutyl, dihydroxybutyl, 2-oxo-propyl, 3-propionaldehyde, perfluorohexyl and the like are examples of such substituted alkyl and alkoxy groups.
• alkenyl embraces unsaturated hydrocarbon residues from 2 to 6 carbon atoms inclusive containing a double bond such as vinyl, allyl, butenyl and the like.
• the alkenyl chain is optionally substituted by one or more substituents, such as, for example, cyano acryloyl, and heterocyclyl, as defined below.
• cycloalkyl embraces cyclic alkyl groups with preferably 3-6 carbon atoms, which can be substituted with functional groups and substituents as mentioned under alkyl and alkoxy.
• bicyclyl groups are adamantyl or bicyclo[2.2.1]hept-2endo- and/or 2exo-yl.
• aryl denotes 6-membered mono- or poly-nuclear aromatic groups with preferably 6-14 carbon atoms. Examples of such groups are phenyl, naphthyl, anthryl and phenanthryl, which can be substituted by one or more substituents. Suitable substituents for ether mentioned aryl groups are e.g. phenyl; lower alkyl (e.g. methyl); substituted lower alkyl as provided for above (e.g. trifluoromethyl, pentafluoro ethyl); C 3-6 cycloalkyl (e.g.
• cyclopropyl hydroxy; cyano; thiocyanato; amino; hydroxyalkyl, optionally esterified with amino acids or sulphuric acid (such as, for example, 2-amino-propionic acid ester or 2-amino-5-guanidino-pentanoic acid ester); halogen (e.g. chlorine); lower alkoxy (e.g. methoxy, n-butoxy); substituted lower alkoxy as described above; lower alkoxycarbonyl (e.g. methoxycarbonyl); di(lower alkyl)amino (e.g.
• dimethylamino, diethylamino carbamoyl, mono- or di-lower-alkylcarbamoyl; lower-alkylsulphanoyl, (e.g. methylsulphanyl); lower-alkylsulphonyl, (e.g. methanesulphonyl); sulphamoyl, N-mono- or di-lower alkylsulphamoyl; heterocyclyl, or with heterocyclyl-lower-alkyl.
• lower-alkylsulphanoyl e.g. methylsulphanyl
• lower-alkylsulphonyl e.g. methanesulphonyl
• sulphamoyl N-mono- or di-lower alkylsulphamoyl
• heterocyclyl or with heterocyclyl-lower-alkyl.
• aryl can be substituted by two vicinal alkoxy groups which form a fused ring, such as, for example, 2,3-dihydro-benzo[1,4]dioxin-6-yl and benzo[1,3]dioxin-5-yl.
• heterocyclyl embraces in the scope of the present invention 4 to 6 membered rings with 1 to 3 N, O and/or S atoms such as, for example, cyclic lactones, cyclic lactames, ketals (such as, for example, 2-dimethyl-1,3-dioxolan-yl), acetals (e.g.
• heterocyclic rings 1,3, dioxolan-2-yl or 1,3,-dioxan-2-yl); examples of such rings are morpholin-4-yl, 4-methyl-piperazin-1-yl, imidazol-1-yl, thiazolyl and [1,2,4] triazol-1-yl, dithianyl, tetrahydropyranyl; the heterocyclic rings can be substituted with substituents described above for the aryl and lower alkyl groups. Such substituents are especially lower alkyl, lower alkoxy, hydroxy, amino, hydroxyalkyl, aminoalkyl or oxo. Pyrrolidinone, methylpyrrolidinone and the like are examples of preferred substituted heterocyclic rings.
• heterocyclyl-lower alkyl embraces in the scope of the present invention heterocyclic rings which are linked via an alkyl residue.
• Preferred heterocyclyl-lower-alkyl units are e.g morpholin-4-ylmethyl, 4-methyl-piperazin-1-ylmethyl, imidazol-1-ylmethyl and [1,2,4]triazol-1-ylmethyl, dioxolan-4yl-ethyl, prrolidinylamethyl, pyperidinylmethyl and the like.
• the heterocyclyl and lower alkyl groups can each be unsubstituted or substituted as provided for above.
• heteroaryl denotes in the scope of the present invention 5- or 6-membered, mono- or poly-nuclear heteroaromatic groups with preferably 5-13 carbon atoms and 1-4 hetero atoms, preferably nitrogen, oxygen and/or sulphur atoms.
• These groups can also be linked with a fused ring, preferably a phenyl ring.
• linked rings are, for example, benzopyranyl, benzofuranyl, indolyl and quinolinyl.
• the heteroaryl groups can be substituted, for example with substituents as described above for the aryl and lower alkyl groups. Additionally, heteroaryl can be substituted by two vicinal alkoxy groups which form a fused ring, such as, for example, [1,3]dioxolo[4,5-b]pyridin-6-yl.
• halide or halogen refer to chloride or chlorine, fluoride or fluorine, bromide or bromine, and iodide or iodine.
• R 1 is preferably methoxy
• R 2 is preferably hydroxy, lower alkoxy such as e.g. methoxy or ethoxy; or lower alkoxy substituted by lower alkoxy such as e.g. methoxymethoxy, lower alkoxy substituted by heterocyclyl such as e.g. morpholin-4-yl-ethoxy or lower alkoxy substituted by lower alkoxycarbonyl-lower alkyl, preferably methoxycarbonylmethyl.
• Preferred lower alkyl groups R 3 include the following groups: methyl (Ex. 1.32, 1.33, 2.11); ethyl (Ex. 2.13); propyl (Ex. 1.30, 1.31, 2.15, 2.16); 3-methyl-butyl (Ex. 2.17); tert.butyl (Ex. 1.23).
• Preferred substituents for the lower alkyl residue R 3 include the following substituents:
• hydroxy such as e.g. hydroxypropyl (Ex. 2.18), hydroxybutyl (Ex. 2.20), 3,4-dihydroxybutyl (Ex. 16);
• methylsulfanyl such as e.g. methylsulfanylmethyl (Ex. 1.17); fluoro such as e.g. tridecafluorhexyl (Ex. 2.3);
• carbamoyloxy such as e.g. carbamoyloxy-butyl (Ex. 2.21), carbamoyloxy-propyl (Ex. 2.22);
• thiocyanato such as e.g. thiocyanatobutyl (Ex. 11);
• --SO 4 H such as e.g. sulfatobutyl (Ex. 10.2) or
• heterocyclyl such as e.g. [1.3]dioxolan-2yl-ethyl (Ex. 2.23), [1.3]dioxolan-4yl-ethyl (Ex. 4).
• heterocyclylcarboyloxy such as e.g. morpholinylcarbonyloxybutyl (Ex. 2.19).
• Preferred substituents for the alkenyl-residue R 3 include the following substituents:
• cyano such as e.g. cyanobutenyl (Ex. 13.1);
• acryloyl such as e.g. acryloylbutenyl (Ex. 13.2).
• Preferred lower cycloalkyl groups R 3 include the following groups: cyclopropyl (Ex 1.46 1.52, 1.53), cyclobutyl (Ex. 1.56), cyclopentyl (Ex. 1.57), cyclohexyl (Ex. 1.60).
• a preferred substituent for the cycloalkyl residue R 3 is the oxo-group such as e.g. cyclopentanone (Ex. 1.9), cyclohexanone (Ex. 1.10).
• Preferred heterocyclyl- or substituted heterocyclyl-residues R 3 include: dithian-2-yl (Ex. 1.49) or tetrahydropyran-2-on 1 (Ex. 1.14).
• aryl-Q-alkyl examples include: phenylsulfonylmethyl (Ex. 1.69) or Phenylsulfinylmethyl (Ex. 2.5).
• Preferred aryl groups R 3 include phenyl or biphenyl, most preferred phenyl.
• the phenyl residue can be mono, di-or tri substituted by the following groups:
• lower alkyl such as e.g. methyl (Ex. 1.19, 1.22, 1.25, 1.40, 1.41), ethyl (Ex. 1.20), butyl (Ex. 1.3), tert.butyl (Ex. 1.18);
• substituted lower alkyl such as e.g. hydroxymethyl (Ex. 2.6, 2.8, 2.9, 3.3, 8.3), hydroxy-ethyl (Ex. 1.68, 2.12), methoxymethyl (Ex. 1.71), trifluormethyl (Ex. 1.58), dimethylaminomethyl (Ex. 1.7), diisopropylamino-methyl (Ex. 1.72), 2-aminopropionylmethyl (Ex. 9.1), carbamoyloxymethyl (Ex. 2.14);
• halogen preferably fluoro (Ex. 2.1, 2.2), chloro (Ex. 1.73);
• lower alkoxy such as e.g. methoxy (Ex. 1.61, 32.3);
• substituted lower alkoxy such as e.g. hydroxyethoxy (Ex. 32.11), trifluormethoxy (Ex. 1.21), 1-ethoxy-ethoxy (Ex. 1.35), 2-ethoxy-ethoxy (Ex. 1.39);
• lower alkoxy-carbonyl such as e.g. tert.butoxy carbonyl (Ex. 1.65); heteroaryl such as e.g. prrrol-1-yl (Ex. 1.42);
• heterocyclyl-lower alkyl such as e.g. 4-methyl-piperazin-1-ylmethyl (Ex. 1.75), 4-morpholin-4-yl-methyl (Ex. 1.76).
• Preferred heteroaryl groups R 3 include pyridyl (Ex. 1.51, 1.2, 32.8) pyrimidinyl, thiophen-2-yl (Ex. 1.66), 5,6-dihydro-4H-pyran-2-yl (Ex. 1.24), furan-2-yl (Ex. 1.28, 1.29, 1.4, 3.2, 8.2), thiazol-2-yl (ex. 1.5), [1,3]dioxolo[4,5-b]pyridin-6-yl (Ex. 32.13).
• the heteroaryl groups R 3 can be mono, di-or tri substituted by the following groups:
• lower alkyl such as e.g. methyl (Ex. 1.37, 1.43, 1.44, 1.48, 1.67, 1.8, 32.1, 32.2, 32.4, 32.5), ethyl (Ex. 34.1);
• substituted lower alkyl such as e.g. hydroxymethyl (Ex. 32.7), hydroxy-1-methyl-ethyl (Ex. 1.78);
• halogen preferably chloro (Ex. 1.59), bromo (Ex. 32.9);
• lower alkoxy such as e.g. methoxy (Ex. 1.74, 32.10, 32.12);
• substituted lower alkoxy such as e.g. methoxy-ethoxy (Ex. 32.15), methoxy-ethoxy-ethoxy (Ex. 32.16), hydroxy-ethoxy (Ex. 32.14), hydroxypropoxy (Ex. 32.17), 2-morpholin-4-yl-ethoxy (Ex. 32.19), dimethylamino-ethoxy (Ex. 32.20);
• heterocyclyl such as e.g. morpholin-4-yl (Ex. 1.79)
• Preferred compounds of formula I are those in which R 1 and R 2 signify lower-alkoxy, especially methoxy; R 3 signifies phenyl, or substituted phenyl or furyl, or lower-alkoxy.
• the compounds of formula I in which R 3 is different from hydrogen can be present in racemic form or as the R- or S-enantiomer. Examples of preferred compounds of formula I are:
• R 3 is pyridin-yl or pyrimidinyl which is substituted by lower alkyl such as e.g.
• the compounds of formula I form pharmaceutically acceptable acid addition salts with organic and inorganic acids.
• acid addition salts of compounds of formula I are salts with mineral acids, for example hydrohalic acids, such as hydrochloric acid, hydrogen bromide and hydrogen iodide, sulphuric acid, nitric acid, phosphoric acid and the like, salts with organic sulphonic acids, for example with alkyl- and aryl-sulphonic acids such as methanesulphonic, p-toluenesulphonic, benzen-sulphonic acid and the like, as well as salts with organic carboxylic acids, for example with acetic acid, tartaric acid, maleic acid, citric acid, benzoic acid, salicylic acid, ascorbic acid and the like.
• a so-called “Heck reaction” is carried out by e.g. reacting a starting compound of formula II in which the leaving group Y represents, for example, bromine, iodine, methanesulphonyloxy, trifluoromethanesulphonyloxy, benzenesulphonyloxy or p-toluenesulphonyloxy with a compound of general formula III.
• an inert organic solvent e.g. dioxan, tetrahydrofuran, N,N-dimethylacetamide or N,N-dimethylformamide, is used.
• the reaction is preferably effected in the presence of a base such as alkali metal carbonate or hydrogen carbonate, e.g. potassium carbonate or sodium hydrogen carbonate, and/or a tertiary amine, e.g. in a tri(lower alkyl)amine such as triethylamine, tri-n-butylamine or N-ethylpiperidine, and together with a catalyst, preferably a palladium complex, such as palladium(II) acetate, bis(triphenyl-phosphine) palladium(II) dichloride, bis(triphenyl-phosphine)palladium(TT) di acetate, tetrakis-triphenylphosphine palladium, or copper(I) iodide and triphenylphosphine or tri-o-tolylphosphine, optionally with the addition of a phase transfer catalyst such as a tetraalkylammonium salt,
• reaction products of formula I groups R 3 which contain alcohol functions can be transformed into an ester.
• Making the salts of the compounds of formula I in accordance with variant c) can be effected in a manner known per se, e.g. by reacting a compound of formula I with an organic or inorganic acid, conveniently in a solvent such as acetone, ethanol, methanol or water.
• reactive acrylic acid derivatives are the acid halides, especially the acid chloride, reactive amides, such as, for example, the imidazolide, and mixed anhydrides.
• the acylation in accordance with the invention can be carried out in an inert solvent, e.g. a hydrocarbon such as benzene or toluene, a chlorinated hydrocarbon such as chloroform or methylene chloride, or an ether such as dioxan or tetrahydrofuran, in the presence of a base, e.g. an amine such as pyridine or triethylamine (which can simultaneously serve as the solvent).
• the reaction temperature is not critical. The reaction is conveniently performed at temperatures between 0° C. and 50° C., especially at 0° C. to 30° C.;
• R 5 is hydrogen, alkyl, alkoxy, aryl or hetrocyclyl, or
• R 4 and R 5 together form --(CH 2 ) n --
• n is a whole number between 2 to 5 inclusive
• R 6 and R 7 are each lower alkyl
• R 6 and R 7 in the case of enamines of formula VI can also together form a ring
• X is a halogen such as e.g. chlorine or bromine.
• This reaction is preferably effected in inert solvents such as ether or in chlorinated hydrocarbons at temperatures of -20° C. to +20° C. with subsequent hydrolysis of the reaction product at 0 to 50° C.
• inert solvents such as ether or in chlorinated hydrocarbons
• M is Li, Na, MgBr, MgCl or MgI.
• This reaction is preferably effected in a temperature range of -80° C. to 20° C.
• An open-chain or cyclic ether such as diethyl ether or tetrahydrofuran is preferably used as the solvent.
• the compounds of formula I and their pharmaceutically acceptable salts possess valuable antibacterial properties. They are active against a large number of pathogenic microorganisms such as e.g. Staphylococcus aureus, Pneumocystis carinii, Strepococcus pneumoniae etc. by virtue of their activity in inhibiting bacterial dihydrofolate reductase (DHFR).
• DHFR bacterial dihydrofolate reductase
• the IC 50 -values (concentration at which the enzyme is inhibited by 50%) are determined by means of a graph.
• the following Table contains inhibitory concentrations determined for representative members of the class of compound defined by formula I and determined in the above test.
• the IC 50 values ( ⁇ M) against the purified DHFR of the reference strain S. aureus ATCC 25923, as well as against the purified DHFR of the multiresistant strain S. aureus 157/4696 are given.
• the third column shows IC 50 values ( ⁇ M) against the purified DHFR of the multiresistant strain Streptococcus pneumoniae 1/1.
• the inhibition constants of trimethoprim are also given as a comparison.
• the products in accordance with the invention can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral or parenteral administration in a variety of unit dosage forms.
• the products in accordance with the invention can be administered perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, or parentally, e.g. in the form of injection solutions.
• Making the pharmaceutical preparations can be affected in a manner which will be familiar to any person skilled in the art by bringing the substances in accordance with the invention, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert therapeutically compatible solid or liquid carrier materials and, if desired, the usual pharmaceutical adjuvants.
• Both inorganic and organic carrier materials are suitable as such carrier materials.
• lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carriers for tablets, coated tablets, dragees and hard gelatin capsules.
• Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers are, however, required in the case of soft gelatin capsules).
• Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and glucose.
• Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils.
• Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.
• the usual preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
• the compounds of formula I and, respectively, their salts are preferably provided as lyophilizates or dry powders for dilution with usual carriers such as water or isotonic saline.
• the compounds of formula I and their salts have antibacterial activity. They inhibit bacterial dihydrofolate reductase and potentiate the antibacterial activity of sulphonamides, such as e.g. sulfisoxazole, sulfadimethoxine, sulfamethoxazole, 4-sulphanilamido-5,6-dimethoxypyrimidine, 2-sulphanilamido-4,5-dimethylpyrimidine or sulfaquinoxaline, sulfadiazine, sulfamonomethoxine, 2-sulphanilamido-4,5-dimetlylisoxazole and other inhibitors of enzymes which are involved in folic acid biosynthesis, such as e.g. pteridine derivatives.
• sulphonamides such as e.g. sulfisoxazole, sulfadimethoxine, sulfamethoxazo
• the ratio of compound I to sulfonamide can vary within a broad range; it amounts to e.g. between 1:40 (parts by weight) and 1:1 (parts by weight); preferred ratios are 1:10 to 1:2.
• a tablet can contain 80 mg of a compound I in accordance with the invention and 400 mg of sulfamethoxazole
• a paediatric tablet can contain 20 mg of a compound I in accordance with the invention and 100 mg of sulfamethoxazole
• syrup per 5 ml can contain 40 mg of compound I and 200 mg of sulfamethoxazole.
• a daily dosage of about 0.2 g to about 2 g of a compound of formula I in accordance with the invention comes into consideration for adults.
• the compounds of formula I are characterized by a high antibacterial activity and a pronounced synergetic affect in combination with sulfonamides and are well tolerated.
• Example 9.1 The educt used in Example 9.1. is prepared as follows:
• Example 9.2 The educt used in Example 9.2 is prepared in analogy to Example 9.1.a) from a 1:1 mixture of (S)-5-(N,N'-bis-tert-butoxycarbonyl-guanidino)-2-tert-butoxycarbonylamino-pentanoic acid (E)-(R)-and -(S)-4-[2-[3-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenyl]-acryloyl]-1,2-dihydro-phthalazin-1-yl]-benzyl ester.
• the pH is adjusted to pH 7-8 using sodium bicarbonate solution and the aqueous phase is extracted three times with dichloromethane/methanol (9:1).
• the organic phase is back-washed with sodium chloride solution, dried over magnesium sulphate, filtered and the filtrate is concentrated.
• the residue is chromatographed on silica gel (eluent: CH 2 Cl 2 /MeOH/NH 4 OH: 9/1/1).
• the pure fractions are combined, concentrated and crystallized from dichloromethane/hexane.
• the crystals are taken up in 150 ml of dichloromethane, stirred and suction filtered.
• the mother liquor is concentrated to about 25 ml and diluted with hexane.
• the crystals obtained are filtered off under suction.
• the educt used in this reaction can be prepared as described in EP-A 0 620 225.
• (+)-enantiomere compounds and (-)-enantiomere compounds respectively can be prepared from the racemic [1H-Phthalazin-2-yl]-propenone by HPLC (e.g. ChiralCell OD). Thus are obtained:
• a solution of 317 mg of acryloyl chloride in 1.5 ml of methylene chloride is slowly added dropwise at 0° C. to a solution of 390 mg of phthalazine and 536 mg of 1-morpholinocyclopentene in 10 ml of methylene chloride.
• the mixture is stirred at 0° C. for 2 hrs., then concentrated, treated with ice-water and made basic by the addition of sodium carbonate.
• the mixture is extracted 3 times with ethyl acetate.
• the organic phases are combined, dried, filtered, the filtrate is concentrated and the residue is chromatographed on 65 g of silica gel; eluent: cyclohexane/ethyl acetate 4:1.
• a solution of 0.53 ml of acryloyl chloride in 3 ml of methylene chloride is slowly added dropwise at 0° C. to a solution of 0.78 g of phthalazine and 1.2 ml of 1-trimethylsiloxy-cyclohexene. After the addition the mixture is stirred at 0° C. for a further 30 min., then concentrated, treated with ice-water and made basic by the addition of sodium carbonate. The mixture is extracted 3 times with 100 ml of ethyl acetate each time. The organic phases are combined, dried over magnesium sulphate, filtered and the filtrate is concentrated.
• a solution of 1 g of phthalazine in 10 ml of methanol is treated at -78° C. with 290 mg of sodium borohydride and stirred for a further 10 min.
• a solution of 0.75 g of acryloyl chloride in 5 ml of diethyl ether is added dropwise at -78° C. during 45 min. and the pale yellow suspension is stirred at -78° C. for a further 1 hr.
• the mixture is poured on to 50 ml of ice-water, treated with 50 ml of a 10% aqueous sodium carbonate solution and extracted with 3 ⁇ 50 ml of methylene chloride.
• dihydro-phthalazines of formula IV used for the preparation of compounds III are generally relatively unstable, oxidation-sensitive compounds, which are often reacted directly in the crude state with acryloyl halides. They can be prepared as described hereinafter or in analogy thereto:
• a solution of 1 g of methyl phenyl sulphoxide in 14 ml of tetrahydrofuran is added dropwise at 78° C. within 10 min. to 3.93 ml of 2M solution of lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene in 20 ml of tetrahydrofuran.
• the reaction mixture is stirred for a further 30 min.
• a solution of 0.928 g of phthalazine in 14 ml of tetrahydrofuran is added dropwise within 10 min.
• the mixture is stirred at -78° C. for 1 hr., treated with 100 ml of water and extracted 3 times with 50 ml of chloroform.
• the starting material used above are prepared as follows:
• compositions can be produced in a manner known per se according to the following formulations:

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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Saccharide Compounds (AREA)

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• 1998
  • 1998-02-24 DE DE69815072T patent/DE69815072T2/de not_active Expired - Lifetime
  • 1998-02-24 KR KR1019997007967A patent/KR20000075888A/ko not_active Ceased
  • 1998-02-24 JP JP53811598A patent/JP4174077B2/ja not_active Expired - Fee Related
  • 1998-02-24 PT PT98913585T patent/PT966464E/pt unknown
  • 1998-02-24 CN CN98803085A patent/CN1091109C/zh not_active Expired - Fee Related
  • 1998-02-24 ES ES98913585T patent/ES2198705T3/es not_active Expired - Lifetime
  • 1998-02-24 CA CA002281642A patent/CA2281642C/en not_active Expired - Fee Related
  • 1998-02-24 TR TR1999/02140T patent/TR199902140T2/xx unknown
  • 1998-02-24 DK DK98913585T patent/DK0966464T3/da active
  • 1998-02-24 ZA ZA981529A patent/ZA981529B/xx unknown
  • 1998-02-24 AU AU68231/98A patent/AU726836B2/en not_active Ceased
  • 1998-02-24 AT AT98913585T patent/ATE241618T1/de not_active IP Right Cessation
  • 1998-02-24 BR BR9808135-7A patent/BR9808135A/pt not_active IP Right Cessation
  • 1998-02-25 US US09/028,980 patent/US6114330A/en not_active Expired - Lifetime
  • 1998-02-26 AR ARP980100859A patent/AR011879A1/es not_active Application Discontinuation
  • 1998-02-27 PE PE1998000142A patent/PE59699A1/es not_active Application Discontinuation
  • 1998-02-27 CO CO98010856A patent/CO4940508A1/es unknown
  • 1998-03-02 UY UY24913A patent/UY24913A1/es not_active Application Discontinuation
  • 1998-03-02 MA MA24985A patent/MA26475A1/fr unknown
  • 1998-03-03 HR HR97103436.8A patent/HRP980110A2/hr not_active Application Discontinuation
  • 1998-03-03 TW TW087103084A patent/TW464648B/zh active

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